Henk-Jan Aanstoot

Insulin injection regimens and metabolic control in an international survey of adolescents with type 1 diabetes over 3 years: Results from the Hvidore study group

Abstract. The optimal insulin regimen for paediatric patients with type 1 diabetes remains controversial. Therefore this multicentre study was performed in adolescents over a 3-year period to assess metabolic control, severe hypoglycaemia, and weight gain in relation to insulin injection regimens. Out of 2873 children and adolescents in an international survey in 1995, 872 adolescents (433 boys, 439 girls, mean age in 1995 11.3±2.2 years) were restudied in 1998, relating insulin regimens to HbA1c measured in a central laboratory. In addition, the daily dose of insulin, changes in body mass index (BMI), and events of severe hypoglycaemia were evaluated. Over 3 years, the use of multiple injection regimens increased from 42% to 71%: 251 patients remained on twice daily insulin, 365 remained on multiple injections and 256 shifted from twice daily insulin to multiple injections. In all three subgroups an increase in insulin dose, a deterioration of metabolic control, and an increase in BMI were observed. Metabolic control deteriorated less than expected over 3 years during adolescence (HbA1c 1995: 8.7±1.6%; 1998 observed: 8.9±1.6%, HbA1c expected for 1998: 9.0%). BMI increased more than expected, the increase was greatest in patients switching from twice daily to multiple injections, and higher in females compared to males. Conclusion: in this international study, metabolic control was unsatisfactory in many adolescents with type 1 diabetes irrespective of the insulin regimen. No improvement in metabolic control was observed in this cross-sectional survey, over 3 years in any of the subgroups. Even the group switching from twice to multiple injections did not improve blood glucose control and the increase in body mass index was most pronounced in this group. Conclusive evidence, however, should be based on prospectively planned, randomised therapeutic trials in paediatric patients.

The midgestational human fetal pancreas contains cells coexpressing islet hormones

In the fetal development of the mouse pancreas, endocrine cells have been found that express more than one hormone simultaneously. Our objective was to evaluate the existence of such cells in the human fetal pancreas. We found cells coexpressing two of the major pancreatic hormones (insulin, glucagon, and somatostatin) in sections of eight midgestational (12-18 weeks) pancreata and in 0-7% of cells in single-cell suspensions from midgestational pancreata. By electron microscopy, using granule morphology and immunoelectron microscopic techniques, we could confirm these findings and even detect cells containing three hormones. Morphologically different granules contained different immunoreactivities, suggesting parallel regulation of hormone production and packaging. In six newborn pancreata (born after 22-40 weeks of gestation), we could not find any multiple-hormone-containing cells. Subsequently, we evaluated whether multiple-hormone-containing cells proliferate by using pancreatic fragments and single-cell preparations at the light and electron microscopic level (six pancreata). No endocrine hormone-containing cells incorporated bromodeoxyuridine during a 1-hr culture period, indicating that these cells have lost the ability to proliferate under the conditions chosen. We conclude that, as in mice, the human fetal pancreas of 12-18 weeks of gestation contains endocrine cells that express multiple hormones simultaneously. These (multiple) hormone-containing cells do not seem to proliferate under basal conditions.

Other complications and diabetes‐associated conditions in children and adolescents

Olga Kordonouria, Georgeanna Klingensmithb, Mikael Knipc, Reinhard W Holld, Henk-Jan Aanstoote, Puthezhath SN Menonf and Maria E Craigg,h,i aDiabetes Centre for Children and Adolescents, Children’s Hospital auf der Bult, Hannover, Germany; bDepartment of Pediatrics, The Children’s Hospital and Barbara Davis Centre, University of Colorado, Aurora, CO, USA; cHospital for Children and Adolescents, University of Helsinki, Helsinki, Finland; dInstitute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany; eDiabeter Center for Pediatric and Adolescent Diabetes Care and Research, Rotterdam, the Netherlands; fDepartment of Pediatrics, Jaber Al-Ahmed Armed Forces Hospital, Kuwait, Kuwait; gInstitute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Sydney, Australia; hDiscipline of Pediatrics and Child Health, University of Sydney, Sydney, Australia and iSchool of Women’s and Children’s Health, University of New South Wales, Sydney, Australia

The global burden of youth diabetes: perspectives and potential.

Less than one-fifth of the people in the world who are diagnosed with diabetes receive the level of care required to maintain optimal health and quality of life. With the incidence of both type 1 and type 2 diabetes increasing at an alarming rate, this is a distressing statistic. Despite the existence of effective national and international guidelines, too few children achieve the appropriate levels of care. Effective diagnosis and care for children with diabetes is no less than mandatory. Diabetes care for youth must be compliant with the United Nation’s ‘‘Convention on the Rights of the Child’’, wherein it is recognized that the child is entitled to ‘‘enjoyment of the highest attainable standard of health and to facilities for the treatment of illness and rehabilitation of health’’. This document addresses key aspects of diabetes, its care and the costs of care in youth under the headings of Epidemiology; Organization of Care; Psychosocial Aspects; and Socioeconomic Aspects. The authors’ goals are to create a standard of care’ which, although dependent on local and national potential and possibilities, serves as a benchmark for improved care to children and adolescents. A recurring theme throughout these chapters is that knowledge of the goals of treatment of diabetes and the components of optimal diabetes care are now well established and well expressed in clinical practice guidelines from numerous sources worldwide. The gap that exists between knowledge and practical implementation of this knowledge is confounding progress in delivering optimal care to all individuals with diabetes including children. The epidemiology of diabetes in children is shifting dramatically. An earlier onset of type 1 diabetes is now being observed, but it is the appearance and increasing incidence of type 2 diabetes in young people, once the sole domain of the adult, that is particularly disturbing. The increase of diabetes is closely related to socioeconomic and environmental factors together with a genetic influence. Overweight and obesity due to a shifting balance and quality of food intake and energy output is a primary modifiable risk factor. There is an enormous gap between knowledge and practice of optimal diabetes care, and a major factor in this gap is organization of care. The components of diabetes care being well established, it is clear that delivery of optimal care is the weak point in the process. Whatever the cause or etiology, without proper treatment diabetes is deadly and dangerous to health. Its potential severity warrants timely and effective treatment. Delivery of care has a number of confounding variables including insufficient financial resources to fund specialised healthcare personnel and in some regions, treatments including insulin; inadequate education of people with diabetes and healthcare providers to embrace the principles of optimal care; and lack of understanding of decision makers of the priority represented by diabetes care due to the impact on not only the individual but also society as a whole. The psychosocial impact of diabetes is largely a hidden cost, but a cost that can undo even the best intentions for care. Young people with diabetes are particularly impacted by psychosocial issues because they are facing a future of living with diabetes at high risk if diabetes is not well controlled from the outset. Parents and other family members can also experience psychosocial impact from the ongoing stress associated with meeting the child’s daily standards for care, and the price in human terms of poor care. The impact of diabetes on children has particularly serious consequences for the socioeconomic health of not only the individual but also of all nations due to the compromises now and in the future for the child’s education, future productivity and contributions to society. Barriers to investment in diabetes care must be replaced with informed investment based on an expanded base of evidence of the far-reaching effects and associated costs of diabetes in children. In the face of the significant proportion of children with diabetes who are not receiving effective care – much less those who are never even diagnosed – it is an unfortunate fact that affordable and effective care

Foreword: DAWN Youth--time to make a real difference.

As a chronic disease, diabetes is difficult enough for adults, but is even more of a challenge for children and young people as they need special support to keep it under control. Worldwide, more than 440 000 children aged ≤ 14 yr diagnosed with type 1 diabetes (1), and each year an estimated 70 000 new cases are reported. Unless action is taken to understand and meet their pressing needs for support, many of these young people could face a lifetime of potentially devastating complications that could otherwise be prevented. As 2008 was designated by the International Diabetes Federation (IDF) as the Year of Children and Adolescents, now more than ever is the time to act to improve the lives of children and young people with diabetes, and the families who support them. The DAWN Youth initiative has recognized the great gap between young people’s need for psychosocial support to deal with their diabetes, and what their healthcare systems offer. Since 2007, it has worked to stimulate better psychosocial support for these yound people and their families. Undertaking the largest study of its kind of their unmet needs, DAWN Youth has built a new, far more comprehensive understanding of the issue than ever realized before. This knowledge is now being applied, as later papers in this supplement show, in advocacy for better healthcare, sharing examples of enlightened best practice with healthcare providers, and concrete initiatives to help and enable all sectors involved to make a real difference. Young people with diabetes have the right to expect and deserve a safe and supportive environment at home, in school, with friends, in the community, and at work. Diabetes disrupts the daily lives of affected young people by making them feel different from others around them. It imposes the strict and absolute need to monitor blood glucose levels, take insulin injections and other medication, and balance the effects of exercise and food. Diabetes interferes with the normal needs of childhood and adolescence, including the need to succeed in schoolwork, social needs, and in the challenging transition to adulthood. These needs present a huge burden of discipline and call for maturity that can be beyond the young person’s years. To help these young people and their families cope with this burden, ideally they should have access to support from a multidisciplinary medical and psychosocial team, with professionals who can give both emotional and physical care appropriate to the age of the child. School staff and healthcare professionals also need extra training, in order to gain the understanding to help children with diabetes to reach adulthood with as little additional stress as possible. The support available today to children and their families, even in most developed countries, is far from optimal. Sadly, for children with diabetes in developing countries, the situation is much worse than that. Now is the time to recognize that diabetes affects children and adolescents all over the world, and nowhere is their care ideal. The IDF Youth Charter, published in 2007, sets out a clear vision for improving psychosocial support for children and young people with diabetes, and their

Assessing diabetes‐related quality of life of youth with type 1 diabetes in routine clinical care: the MIND Youth Questionnaire (MY‐Q)

It is recommended to assess health‐related quality of life (HRQoL) in teenagers with diabetes as part of their ongoing medical care. Here, we describe the development and psychometric evaluation of the Monitoring Individual Needs in Diabetes Youth Questionnaire (MY‐Q), a multi‐dimensional self‐report HRQoL questionnaire designed for use in pediatric diabetes care.

Analysis of antibody responses against Coxsackie virus B4 protein 2C and the diabetes autoantigen GAD65.

Type I diabetes mellitus results from the autoimmune destruction of insulin producing beta cells in the pancreas. Certain viral infections, especially those caused by coxsackie B viruses and related enteroviruses, have been associated with the development of type I diabetes. The sequence homology between the coxsackie B4 virus nonstructural protein 2C (CVB4 p2C) and the major diabetes autoantigen glutamic acid decarboxylase (GAD65) provides a basis for the hypothesis of molecular mimicry. In this study, we investigated the prevalence of antibodies directed against nonstructural enterovirus proteins. In addition, a correlation of antibodies against CVB4 p2C and GAD65 was studied in diabetes patients and in healthy controls. Antibody reactivity against CVB proteins was detected by immunoprecipitation of [35S]‐methionine‐labelled viral proteins and GAD65 antibodies were measured in a quantitative radio‐immunoassay. It was shown that antibodies raised against the nonstructural proteins of CVB4 are very common in the population and a high degree of heterotypic cross‐reactivity exists between different enterovirus types. CVB4 p2C‐specific antibodies were not only detectable in GAD65 antibody‐positive diabetes patients but also in GAD65 antibody‐negative healthy blood donors. Furthermore, GAD65 antibodies could not be detected in p2C‐positive subjects who had various enterovirus infections, indicating that an antibody response to CVB4 p2C does not necessarily induce a cross‐reactive immune response against GAD65. A correlation was not found between antibodies against GAD65 and p2C. J. Med. Virol. 59:256–261, 1999.

Absence of a PDX-1 mutation and normal gastroduodenal immunohistology in a child with pancreatic agenesis

Abstract. Pancreatic agenesis is a rare condition, of which only a limited number of cases have been described. One recent paper reported a homozygous mutation in the pancreatic duodenal homeobox gene 1 (PDX-1) in a child with pancreatic agenesis. We report a 6-year-old boy with pancreatic agenesis, treated medically, without abnormalities in the PDX-1 gene coding sequence and with normal gastroduodenal endocrine cell distribution. Genes other than PDX-1 also appear to be involved in human pancreatic agenesis.

DAWN Youth: a direct response to young people's attitudes, wishes, and needs

Aanstoot H‐J. DAWN Youth: a direct response to young peoples attitudes, wishes, and needs.

Changing the future of diabetes

The DAWN Youth International Advisory Group: Henk-Jan Aanstoota, Barbara Andersonb, Thomas Dannec, Larry Deebd, Alexandra Greenee, Francine Kaufmanf, Karin Langeg, Anja Østergren Nielsenh, Mark Peyroti and Kari Rosenfeldj aDiabeter, Center for Pediatric and Adolescent Diabetes Care and Research, Rotterdam, The Netherlands; bBaylor College of Medicine, Houston, TX, USA; cCentre for Children and Adolescents with Diabetes, Kinderkrankenhaus auf der Bult, Hannover, Germany; dUniversity of Florida and Florida State University, FL, USA; eHealth Services Research Unit, University of Aberdeen, Aberdeen, UK; fKeck School of Medicine and Annenberg School of Communications of USC, Children’s Hospital of Los Angeles, Los Angeles, CA, USA; gDepartment of Medical Psychology, Hannover Medical School, Hannover, Germany; hYouth Ambassador, DAWN Youth Advisory Board, and University of Copenhagen, Copenhagen, Denmark; iDepartment of Sociology, Loyola University Maryland, and Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA; and jInternational Diabetes Federation, Brussels, Belgium